There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of Type 2 diabetes. In contrast to what has been a prevailing beneficial view of antioxidants in preventing pancreatic ?-cell dysfunction in diabetes, this project proposes that in response to arsenic exposure, transcription factor Nrf2-mediated adaptive induction of endogenous antioxidant enzymes plays paradoxical roles in ?-cell function. The investigators hypothesize that, on the one hand, Nrf2-mediated antioxidant response blunts glucose-triggered `ROS signaling' that plays an important role in glucose-stimulated insulin secretion (GSIS); on the other hand, the response protects ?-cells from oxidative damage and subsequent apoptosis/necrosis. The investigators propose three specific aims: (1) Test the hypothesis that induction of antioxidant enzymes in response to arsenic exposure and related oxidative stress impedes glucose-triggered `ROS signaling' and thus GSIS; (2) Test the hypothesis in silico that adaptive induction of antioxidant enzymes in response to chronic oxidative stress impedes `ROS signaling', and explore intervention approaches that can improve `ROS signaling'; (3) Test the hypothesis that Nrf2-mediated antioxidant response is critical for protecting ?-cells from oxidative damage and apoptosis/necrosis induced by arsenic and/or glucose toxicity. The integrated wet-lab and computational approaches will allow to: (1) understand how environmental arsenic exposure impairs ?-cell function; (2) characterize the quantitative nature of the effect of arsenic-induced oxidative stress on `ROS signaling' that is involved in GSIS; (3) distinguish the specific roles of Nrf2 and its target antioxidant enzymes in `ROS signaling' and ?-cell function; and (4) identify novel targets and approaches to modulate insulin secretion and protect ?-cells from oxidative damage. This project will investigate the pathogenic mechanisms of Type 2 Diabetes caused by environmental arsenic exposure. The results may enable new therapeutic managements and preventive strategies for arsenic or other environmental oxidative stress-associated diabetes.